We have assembled a team of highly talented individuals who collectively bring to the MMHCC their extensive expertise and/or unique resources for studying prostate cancer in mice, including: (i) generating and analyzing mutant mouse models (Michael Shen), (ii) non-invasive imaging to visualize tumors and metastases (Simon Cherry); (iii) comparative histopathology with human cancers (Robert Cardiff); (iv) analyzing cancer phenotypes (Cory Abate-Shen and Gerald Cunha); (v) functional genomics and proteomics (Peter Nelson); and (vi) translational research (William Nelson). Building upon our expertise and leveraging our previous studies that have generated mouse models that recapitulate stages of human prostate carcinogenesis, we are well-poised to implement an ambitious research program that should yield fundamental insights into basic molecular mechanisms of carcinogenesis and will have considerable clinical relevance. We propose the following projects: Project 1 is designed to produce a "next generation" of mouse models, focusing on advanced stages of prostate cancer. These studies will generate mouse models that combine temporal inducibility with indelible linage marking and multimodal imaging reporters to allow non-invasive whole-animal imaging of metastatic disease. Project 2 will identify novel components of the molecular pathways involved in prostate carcinogenesis, using functional generates and proteomics approaches, and may also lead to the generation of new serological tests for early detection of prostate cancer. Project 3 will address the significance of hormonal signaling for prostate carcinogenesis, and may provide insights into the efficacy and mechanisms of synthetic anti-androgens as chemopreventive agents. Project 4 will develop mouse models to examine the role of oxidative stress in prostate carcinogenesis, and will utilize these mice to test the efficacy of dietary anti-oxidants in a "pre-clinical" trial of chemoprevention. These studies will yield mouse models for longitudinal visualization of metastatic spread in vice, for examination of the temporal requirements of tumor suppressor function, and for investigation of chemoprevention; we will also exploit these mouse models to define prognostic indicators of cancer, and to address other clinically relevant issues that would be intractable using human subjects. Thus, we anticipate that our studies of prostate carcinogenesis in mice should also lead to new general paradigms and/or experimental model systems that arc broadly relevant for understanding human cancer biology.